Plasminogen activating agents including streptokinase, urokinase, tissue plasminogen activator (t-PA), and their analogues have been administered as lytic agents for treatment of arterial and venous thrombosis. Although such agents as t-PA are efficacious for lysis of coronary thrombi and pulmonary emboli, relatively high concentrations are required. (Marder V. J., Sherry S.; "Thrombolytic Therapy: Current Status" N Engl J Med 318:1512-20 (1988). Marder V. J., Sherry S.; "Thrombolytic Therapy: Current Status", N Engl J Med 318:1585-95 (1988). Vaughan D. E., Goldhaber S. Z., Kim J., Loscalzo J.; "Recombinant Tissue Plasminogen Activator in Patients Pulmonary Embolism . . . " Circulation 75:1200-03 (1987).) The need for high concentrations may be due, in part, to the paucity of fibrin binding sites for t-PA on the surface of whole blood clots. In the absence of binding to fibrin, t-PA has greatly reduced efficacy in activating plasminogen and inducing clot lysis. In clinical practice, t-PA can be directly injected into the site of thrombus with percutaneous transluminal catheters rather than infused systemically. Presumably this approach improves lysis by increasing the surface area of fibrin available for t-PA binding.
Ultrasound has been used without exogenous t-PA to disrupt peripheral arterial and venous thrombi in animal models and to open atherosclerotic occlusions of peripheral arteries in selected patients. To achieve these effects, ultrasound was used at a frequency (20 kHz) and intensity that caused cavitation, thereby disrupting tissues with low elasticity, such as atheromas and thrombi. The ultrasound was delivered through catheters to prevent damage to normal tissues near the sites of the occlusions.
Kudo and co-workers are the first to report the use of noninvasive ultrasound to increase the efficacy of systemic t-PA. (Kudo S., Furuhata H., Hara M., Maie K., Hamano K., Okamura T. "Noninvasive Thrombolysis with Ultrasound"; Circulation, 80:supp 1I-345 (1989) (abstract); Kudo S. "Thrombolysis with Ultrasound Effect", Tokyo Jikeikai Med J., 104:1005-1012 (1989); and Hamano K., Fujinaga T., Muto M., Yoshizawa S., Kudo S., Hara M., Okamura T., Furuhata H., "Thrombolysis by Transcutaneous Ultrasonic irradiation, Circulation, 82:III-309 (1990) (Abstract).) It was found that transcutaneous ultrasound that was delivered in a continuous mode at a frequency of 200 kHz could enhance t-PA-induced fibrinolysis in a canine model of femoral arterial thrombi. The instantly disclosed and claimed invention varies from the methods taught in those publications, since the inventive method uses intermittent (pulsed mode) ultrasound and/or a fluid interface between the skin of the patient and the transducer of the ultrasound generator.
Lower extremity deep venous thrombosis (DVT) incidence in the United States is greater than 250,000 cases annually. Pulmonary embolism is the primary cause of at least 50,000 deaths annually. The incidence of clinical DVT is 1 in 500 in general hospital patients. In unselected patients undergoing elective major general or orthopedic surgery without prophylaxis the incidence of DVT is reported to be 20% to 30%.
Heparin is often used to prevent thrombus propagation. Plasminogen activators (PA's) are used to lyse thrombi, but DVT are often resistent to both of these therapies. Complete thrombolysis is difficult to achieve. Plasminogen activators are particularly effective thrombolytic agents when incorporated into a forming thrombus. It is believed that limited surface binding and penetration into the thrombus by PA may explain difficulties in achieving complete thrombolysis.
Raising the dosage of t-PA administered beyond 100 mgm for lysis of acute thrombosis increases the number of hemorrhagic complications and, for this reason, dosing above this level is not desirable.
Most investigation of ultrasound bioeffects have been directed to safe exposure of human for diagnostic purposes. However, therapeutic applications to treat injuries to soft tissue and for ultrasonic aspiration have proven useful in neurosurgery and soft tissue resections. Reports of studies of ultrasound by Kudo on dogs do not discuss some of the problems related to temperature increases arising during exposure for therapeutic uses. No disclosure of use of ultrasound to prevent formation of thrombosis has previously been disclosed.
A model frequently used in assessing thrombosis has been the rabbit with jugular vein thrombosis. Previous studies with this model indicate that the rate and extent of thrombolysis are related and that complete lysis of thrombus is very difficult to achieve. Ultrasound that is used in physiotherapy is delivered at a frequency of 1 MHz, which can cause acoustic streaming, or wave-media interactions that promote agitation of solute and micro-particulate matter without inducing cavitation or tissue damage. This property of ultrasound suggests that it may have the potential for gentle perturbation of a clot, thereby exposing additional fibrin for binding to the plasminogen activator.
Ultrasound travels through fluid and soft tissue by wave propagation. The number of ultrasound waves per unit area is a measure of power which is usually expressed as watts/cm.sup.2. As ultrasound travels through soft tissue it pushes fluids in the direction of the beam. Another effect is the momentary absorption of ultrasound energy by dissolved gases in fluid which results in expansion and then redissolution of the gas. These effects are referred to as acoustic microstreaming and cavitation. The end result of ultrasound interactions with soft tissue is attenuation of the beam and generation of heat. Attenuation increases as frequency increases, which results in a decreasing penetration into soft tissue with increasing ultrasound frequencies. The 1 MHz frequency used in these experiments will maintain 30% of original energy after traversing 10 cm of soft tissue. At power levels of 3.0 watts/cm.sup.2 (average power), harmful effects of ultrasound have been noted only under conditions which generate enough heat to cause thermal injury.
Clinical experience with plasminogen activators have resulted in findings similar to those noted in rabbit studies. The greatest success has been attained in treatment of coronary artery thrombi, but challenges remain: 1) to decrease the mean time required for restoration of coronary artery flow following administration of the plasminogen activating agents and 2) in the setting of acute myocardial infarction or venous thrombosis, to increase the percent of patients receiving plasminogen activators who will have successful restoration of blood flow. Raising dosage of plasminogen activators increases the number of hemorrhagic complications and, for this reason, dosing at high levels is not a routine option to improve results of therapy.